Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-06-20
1999-02-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C07D47104, A61K 3144
Patent
active
058665889
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds which are dual histamine (H.sub.1) and platelet activating factor (PAF) receptor antagonists, to therapeutic compositions containing such compounds, and to methods for their preparation.
BACKGROUND TO THE INVENTION
Potent H.sub.1 receptor antagonists of various structural types are known, and are useful in treating the symptoms of inflammatory conditions such as allergic rhinitis, and allergic conditions of the skin, which are mediated at least in part by the release of histamine. However, in such conditions, in which histamine release plays a causative role, there may be other mechanisms at work which are not inhibited by treatment with an H.sub.1 receptor antagonist alone. For example PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a wide variety of physiological responses, including hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, increased vascular permeability (oedema/erythema), and accumulation of inflammatory cells in the lower airways.
There is therefore a need for agents which have dual H.sub.1 and PAF receptor antagonistic activity for the improved treatment of conditions mediated by histamine and PAF release. Such conditions include allergic rhinitis, sinusitis, asthma, dermatitis, psoriasis, urticaria, anaphylactic shock, conjunctivitis, pruritis, inflammatory bowel disease and colitis.
European patent specification EP-B-404797 (G. D. Searle) claims a series of PAF receptor antagonists of general formula (I) ##STR2## wherein Y, R.sup.1 and R.sup.2 are as defined in the publication itself.
International patent applications WO-A-92/03423 (British Biotechnology) and WO-A-9516687 and U.S. Pat. No. 5,180,724 (British Biotechnology) disclose which are potent antagonists of the PAF receptor.
U.S. Pat. No. 2,712,020 (Burroughs Wellcome) and European patent applications EP-A-085959 and EP-A-133534 (Wellcome Foundation) disclose compounds which are potent H.sub.1 receptor antagonists.
International patent applications WO-A-92/14734 (Pfizer), WO-A-92/00293 (Schering), WO-A-89/10363 (Schering), WO-A-93/20080 (Schering), WO-93/20063 (Schering), WO-A-93/23400 (Schering), WO-A-93/02081 (Schering), WO-A-94/08581 (Toray), European patent applications EP-A-515158 (Schering), EP-A-463873 (Sankyo), EP-A-549364 (Sankyo), EP-A-577957 (Uriach) and Japanese patent application published under no 4-226993 (Yoshitomi) all disclose compounds which possess both histamine (H.sub.1) and PAF receptor antagonist activity.
BRIEF DESCRIPTION OF THE INVENTION
The invention makes available a class of compounds with some of the structural features of the potent PAF receptor antagonists of WO-A-92/03423 and U.S. Pat. No. 5,180,724, and structural features of H.sub.1 receptor antagonists of for example U.S. Pat. No. 2,712,020, united in a single molecule in such a way as to provide a desirable balance of H.sub.1 and PAF receptor antagonist activity. Furthermore, it has been shown that, in such compounds the structural features of the histamine fragment are also important for providing high affinity for the PAF receptor.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention there is provided a compound of formula (II) ##STR3## wherein: L and A are such that (i) L represents an unbranched saturated or unsaturated divalent hydrocarbon chain having up to 6 carbon atoms and A represents a bond, or (ii) L represents a bond or --CH.sub.2 -- and A represents a divalent 1,4-phenylene group which may be substituted by C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, cyano, halogen or C.sub.1 -C.sub.6 alkoxy; hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl or non-aromatic 5 to 7 membered heterocyclyl, any of which which may be substituted with one or more C.sub.1 -C.sub.6 alkyl, --(C.dbd.O)O(C.sub.1 -C.sub.6 alkyl), --COOH, or phenyl groups; alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.8 cycloalkyl or non-aromati
REFERENCES:
patent: 4621094 (1986-11-01), Findley et al.
patent: 5180724 (1993-01-01), Bowles et al.
Ayscough Andrew Paul
Blackwell Christopher Mark
Launchbury Steven
Whittaker Mark
British Biotech Pharmaceuticals Ltd.
Kessinger Ann M.
Shah Mukund J.
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